Squamous cell carcinoma of the head and neck (SCCHN) has an incidence rate of >40,000/year in the US. It is the fourth most common malignancy among males. Patients with SCCHN are afflicted with a disease that profoundly influences their quality of life and some essential functions, including breathing, eating, and communication. Treatment of SCCHN does not always improve these serious functional deficits, and, in many instances, the treatment itself results in further deterioration of these functions. Clearly, patients need an effective but less debilitating treatment, such as gene therapy, for SCCHN. The long-term goal is to develop a simple and effective strategy for eradicating SCCHN. The immediate goal of this project is to determine if electroporation of the IL-12 gene in combination with a tumor- and endothelium-targeted cytotoxic gene will eradicate heavy-load tumors in a mouse model. We have pioneered the use of electroporation as a novel and simple approach for treatment of squamous cell carcinoma in a mouse model. Head and neck cancer is directly accessible by needle electrode and the extension of the needle length allows treatment of deep tumors. The hypothesis for the proposed study is that electroporation of IL-12 and a tumor-targeted cytotoxic gene into tumors will eradicate heavy-load SCC. To test this hypothesis, a tumor- and endothelial-cell double-targeted cytotoxic gene will be generated. Then, the biochemical and biological function of this fusion gene will be evaluated in vitro and in vivo. Following that, the therapeutic effects of combining IL-12 and this tumor targeted gene therapy will be evaluated. The application has a high probability of success because an excellent model system is in place to test the hypothesis, and the investigators have extensive experience in the electroporation gene therapy field and the resources necessary to complete the tasks. This work holds enormous potential for progress in eradicating SCC.